1. Field of the Invention
Interactions between molecules form the basis of most biological processes; understanding these interactions is important for the development of applications in basic research and medicine. For example, many drugs act by binding to specific receptor molecules. The task of finding ligands that bind to a given target with high specificity and affinity is often difficult and though the introduction of combinatorial chemistries will make this task easier, it is likely that single ligands for a single biological target may not be effective enough for some purposes; for example, where the aim is to block completely a specific process.
The present invention describes novel ways of discovering combinations of ligands which act together to produce more specific and stronger interactions than can be achieved by a single ligand.
2. Description of Related Art
There are two distinct ways in which ligands could act cooperatively:
Many biologically important macromolecules or macromolecular assemblages, such as proteins and RNA, are held in their active conformation by intramolecular interactions based on weak forces. Binding one ligand to the molecule partially opens its structure, and, as we will show, may expose it to other ligands which cannot bind in the absence of the first ligand. These additional ligands will reinforce the attenuation of the target molecule. PA1 Many biological processes occur as a result of a series of reactions, each one dependent on a different macromolecule; for example, most of the pathways that produce metabolites involve a series of steps catalysed by a number of enzymes. Each enzyme could be targeted by a different ligand to produce a greater effect on the flux through the pathway than would be produced by any one. A further benefit of using combinations of agents is that it would prevent the development of resistance to the therapy: it is a major problem in the use of antibiotics and anticancer agents that, after a time, resistance develops as a result of mutation. If the agents comprised a mixture that targeted different molecules in the cell, multiple mutations would be required to produce resistance. Clearly, the chance of a cell undergoing two random mutations that coincide two produce resistance to two agents is much less likely than the single mutation required to overcome the effects of a single agent.